PHARMACOLOGY OF ANESTHETICS LA+GA_MKG.pptx

Anesthetics PPT by DR MUKESH GUPTA for pharma students

1. Local Anaesthetics By Dr. Mukesh Gupta

2. ANAESTHESIA : GENERAL ANAESTHESIA LOCAL ANAESTHESIA Actions GA LA Site of action CNS Peripheral nerves Body involved Whole Particular area Consciousness Lost Altered Care of Vital function Needed Not needed Surgery Major Minor Expert Essential Not

3. Anesthesia Types Local Anesthesia : are drugs which, when applied directly to peripheral tissue, block the nerve conduction and abolish all sensations in the part supplied by the nerve without loss of consciousness or reversible loss of sensory perception LA causes the local loss of pain, temperature, touch, pressure and all other sensation . NOTE - Loss of sensation without inducing loss of consciousness. Regional Anesthesia : loss of sensation over a specific region of the body (e.g. lower trunk) General Anesthesia : loss of sensory perception of the entire body

4. Long action Medium action Short action Long action (bupivacaine, ropivacaine) (lidocaine) (procaine) (tetracaine) Local Anesthetics Surface action (benzocaine, cocaine) Note: The choice of “which” LA to use clinically is often based upon its duration of action Esters Amides (Novocaine ®) (Xylocaine ®)

5. Features of LA Quick onset of action Not irritating to skin & mucous membranes Duration of action must be long enough to allow desired surgery to be completed Effective on both injection & local application Low Systemic toxicity Should not cause any permanent damage on any tissue. Should be relatively free from producing allergic reaction. Should be stable in solution and readily undergo biotransformation .

6. LA Chemistry Amide vs. Esters Cocaine Procaine Benzocaine Tetracaine Lidocaine Bupivacaine Mepivacaine Ropivacaine * Except for Benzocaine Amides Am i des: “ i ” before “ caine ” LA’s - tertiary amines*

7. ADVANTAGES OF AMIDES OVER ESTERS Produce more intense and longer lasting anaesthesia . Bind to α 1 acid glycoprotein in plasma. Not hydrolysed by plasma esterases . Rarely causes hypersensitivity reaction

8. Mechanism of Action Hydrophobicity increases potency & duration of action (bupi > lido> procaine) Frequent openings = enhanced block (use dependent block) Inflammation : extracellular acidosis = decreased LA effect

9. MOA - LA ( lignocain ) Bind voltage gated Na Channels Block Na entry into the cell NO generation and conduction of AP Loss of sensation (ANEASTHESIA ) MAO

10. LA closed the gate for Na ion, inhibit exchange- signal not passing to other neuron. At high dose It block Ca and K ion channels. MOA

11. Pharmacological action LA applied locally but ultimately absorbed in systemically and produced following functions according to concentration . CNS - Firstly stimulation then Depression of cortical region which result drowsiness, lathargy , twitching of muscles, convulsion and generalized CNS depression CVS - At high dose shows - ve ionotropic, - ve chromo and dromotropic (Na channel blocker), cardiac depressants, causes cardiac arrhythmia. BV - Hypotension due to sympathetic blockade but at high concentration, cause direct relaxation of arteriolar SM. Bupivicaine is more vasodilatations then Lidocaine . Toxic dose of LA cause cardiovascular collapse SM - Reflex action on vascular, bronchial muscles and bowel SM

12. Kinetics Soluble a naesthetics are r apidly a bsorbed f rom Mucous membrane and abraded skin . T he rate of absorption depends on the vascularity of the area. LA (ester linked) are hydrolyzed by plasma pseudocholinesterase & remaining by esterase in liver. They showed high first pass effect.

13. Factor effecting on LA 1.Effect of pH : Active in alkaline PH 2.Effect of lipid solubility: highly lipophilic LAs penetrate the nerve membrane more easily. So more potent . 3.Effect of diffusibility :  diffusibility → time of onset 4.Effect of protein binding:  binding →  duration of action

14. Uses - Surface anesthesia –for mucous membrane of eye, nose, mouth, brochial , oesophagus , UTI etc as anesthetic solution by direct application. Tetracain - 2% Lignocaine – 2-10% Proparcain – 0.5% Benoxinate - 0.4% Benzocain - 1-5% As spinal anesthesia- L 2-3 or L 3-4 (into subarachnoid space) Epidural anesthesia In Nerve block Infiltration anesthesia Conduction block Most used

15. Conduction block Nerve block Epidural Block Infiltration

16. Adverse effect Dizziness, confusion, anxiety, respiratory depression Hypotension, bradycardia Rashes, dermatitis, anaphylaxis

17. NA with LAs Epinephrine (NA) can be combined with LAs to- Vasoconstriction ( α 1) of NA causes Prolongs duration of action of LAs by decreasing rate of removal from local site into circulation Decrease systemic toxicity (  uptake by up to 1/3) Enhances intensity of nerve block Prolong local anesthesia (by ~50%) Decrease local bleeding (improve visualization of surgical field) Vasoconstrictor ( Adr ) containing LA should be avoided for patients with ischemic heart disease, cardiac arrhythmia, uncontrolled hypertension those receiving β -blockers or tricyclic antidepressants

18. LA toxicity Numbness of tongue & mouth Behavioral & sensory disturbances ringing in ears, metallic taste, tingling sensations Seizures (tonic clonic ) Depression / Loss of Consciousness Respiratory Failure, Arrhythmias*,CV Collapse Warning signs Lawsuit Rx : succinylcholine / diazepam i.v ., O 2 , Na Bicarb *

19. Order of sensory function block 1. pain 2. cold 3. warmth 4. touch 5. deep pressure 6. motor Recovery in reverse order

20. General Anaesthesia By Mukesh G upta

21. DIFFERENCES BETWEEN G A & LA FEATURES Gen.Anaesthsia Local Anaesthsia Site of action CNS Peripheral nerves Area of body involved Whole body Restricted area Consciousness Lost Unaltered Care of vital functions Essential Usually not needed Poor health patients Risky Safer Use in non cooperative patients Possible Not possible Major surgery Preferred Cannot be preferred Minor surgery Not preferred preferred

22. Definition : General Anesthesia is the reversible loss of response to & perception of all external stimuli. Components of General Anesthesia : 1.Loss of conciousness 2. Sleep & amnesia 3. Immobility & muscle relaxation 4. Abolition of reflexes . These drugs are generally administered by an anesthesiologist in order to induce or maintain general anesthesia to facilitate surgery.

23. Phases of Anesthesia Induction : putting the patient to sleep Maintenance : keeping the patient asleep Emergence : waking the patient up

24. Gas Volatile liquids * Barbiturates Misc. Opioids Benzodiazepines (nitrous oxide) (halothane isoflurane, desflurane , sevoflurane ) Eather (thiopental) (midazolam) (fentanyl) ( ketamine,metomidate , propofol ) General Anesthetics Inhalational Parenteral *In the beginning there was ether & chloroform

25. Mechanisms of Action Enhanced GABA effect on GABA A Receptors Inhaled anesthetics - Etomidate Barbiturates - Propofol Benzodiazepines Block nicotinic receptor subtypes (analgesia) Moderate to high conc’s of inhaled anesthetic Eg-propofol Activate K channels ( hyperpolarize V m ) Nitrous oxide, ketamine, xenon Inhibit NMDA (glutamate) receptors Nitrous oxide, ketamine, xenon, high dose barbiturates

26. CNS Effects Increasing dose Coma Barbiturates Benzodiazepines Hypnosis Sedation, disinhibition, anxiolysis Possible selective anticonvulsant & muscle-relaxing activity Dose Response Relationships Anesthesia Medullary depression

27. Minimum Alveolar Concentration MOA of GA is not clear but common physiochemical property by which all GA are working that is lipid:water partition coefficient. The minimum alveolar anesthetic concentration (MAC) required to eliminate the response to a painful stimulus in 50% of patients It’s “a population average ”. MAC tells about the depth of anesthesia Alveoli ======== Blood======== Brain A measure of GA potency by the capacity to enter into CNS and attain the sufficient concentration in neuronal membrane for limited time.

28. GA generally given as combination which causes additive to MAC values (e.g. nitrous oxide is commonly mixed w/ other anesthetics ). Advantage of combinations: Supplement general anesthesia Maintain general anesthesia Provide sedation Control blood pressure Protect the brain

29. Elimination Anesthesia is most commonly terminated by redistribution of drug from brain to the blood & out through the lungs. The rate of recovery from anesthesia for GAs with low blood:gas Partition Cs is faster than for highly soluble Gas . - Blood:Gas PCoeff Haltothane 2.30 Desflurane 0.42 Sevoflurane 0.69 Halothane & methoxyflurane undergo hepatic metabolism & can cause liver toxicity .

30. ClassicAL Stages of Anesthesia* Stage 1 : Analgesia decreased awareness of pain, amnesia, used in – labour pain, other minor operation Stage 2 : Delirium delirium & excitation, enhanced reflexes, regular respiration, involuntary activity, PATINENT may shout, jerky breathing, HR rise, pupil dilate..etc not used in ops. Stage 3 : Surgical Anesthesia unconscious, no pain reflexes, irregular respiration, BP is maintained PLANE 1- Roving eyebolls Plane 2- Loss of corneal and laryngeal reflex Plane 3- Pupil starts dilating, light reflex lost Plane 4 – Intercostal paralysis, dilated pupil

31. Stage 4 : Medullary Depression/paralysis Cessation of breathing, respiratory failure & CV depression, muscles are totally flabby, requiring ventilation & pharmacologic support . it is seen only with overdose.

32. Barbiturates Thiopental & methohexital are highly lipid soluble & can produce unconsciousness & surgical anesthesia in <1 min. Rx: induction of anesthesia & short procedures Actions are terminated by redistribution With single bolus - emergence from GA occurs in ~ 10 mins Hepatic metabolism is required for elimination Contradicted- Barbiturates are respiratory & circulatory depressants so, it Contraindicated : in hypovolemia, cardiomyopathy, beta-blockade , etc. Note- It causes Psychomotor impairment for days after use of a single high dose. Not given in any i.v drug till barbiturates cleared.

33. Propofol ( Diprivan ®) Produces anesthesia works as rapidly as i.v.tiopenton & but recovery is more rapid than barb’s . due to more rapid clearance. Unconsciousness in 15-45 second after injection, recover after 10 minutes. Patients are able to ambulate sooner & patients “feel better” in the post-op period compared to other i.v. anesthetics. It is fast metabolized then others, HL is 2-4 min Can cause marked hypotension Commonly used as component of “balanced anesthesia” for maintenance of anesthesia. Pain during injection, bu minimized by lidocaine .

34. Ketamine A “ dissociative anesthetic ” that produces a cataleptic state that includes intense analgesia , amnesia with light sleep, eyes open, involuntary limb movement, unresponsive to stimuli or pain. Pharmacogically related to hallucinogen. Patient appears to be dissociate from own body and surroundings. Primary site of action is cortex and sub cortical areas Increases heart rate & blood pressure ( opposite of other GAs ) Onset of action is within in min. and recovery starts after 15 min. but patients in amentia with light sleep for 1-2 hr . Dose- 1-3 mg/kg, injection is not painful Ketamine generally employed in dental surgery like head and neck

35. Used in: C hildren & young adults for short procedures. Head and neck surgery, burn, dressing etc. Can be used in shock states (hypotensive) or patients at risk for bronchospasm . Side Effects : pupillary dilation, salivation, hallucinations & vivid dreams, hypertention .

36. Conscious Sedation Monitored the consciousness to carry out the diagnostic or short or dental operations Operative procedures performed with minimal physiological and psychological stress. Drugs are used to produce states of CNS depression, but in consciousness, and maintain the patient airway. In this protective airway and other reflexes are not lost, as in GA. Drugs in CS- Diazepam, Propofol , N2O, Fantynyl

37. Properties of Inhaled anesthetics Nitrous Oxide MAC > 100% : Incomplete anesthetic Good analgesia No metabolism Rapid onset & recovery Used along w/ other anesthetic; fast induction & recovery Halothane The first halogenated inhalational anesthetic Not pungent ( use for induction w/children )* Medium rate of onset & recovery Although inexpensive, its use has declined Sensitizes the heart to epi -induced arrhythmias Rare halothane induced hepatitis * fewer side effects also seen in children

38. Desflurane Most rapid onset of action & recovery of the halogenated GAs (low PC) Widely used for outpatient surgery Irritating to the airway in awake patients & causes coughing, salivation & bronchospasm ( poor induction agent ) Used for maintenance of anesthesia Sevoflurane Very low blood:gas partition coefficient w/ relatively rapid onset of action & recovery * Widely used for outpatient surgery* Not irritating to the airway Useful induction agent , particularly in children * Similar to Desflurane

39. Isoflurane Medium rate of onset & recovery Used for induction & maintenance of anesthesia Isoflurane “was” the most commonly used inhalational GA in the US. Has been largely replaced by Desflurane . Methoxyflurane Now widely considered obsolete Slow onset & recovery Extensive hepatic/renal metabolism, w/ release of F - ion causing renal dysfunction

40. Toxicity Malignant Hyperthermia Esp. when halogenated GA used with succinylcholine Rx: dantrolene (immediately) Halothane: Halothane undergoes >40% hepatic metabolism Rare cases of postoperative hepatitis occur Halothane can sensitize the heart to Epi (arrhythmias) Methoxyflurane F release during metabolism (>70%) may cause renal insufficiency after prolonged exposure. Nitrous oxide Megoblastic anemia may occur after prolonged exposure due to decreases in methionine synthase activity ( Vit B 12 deficiency).

41. NMJ Blockers Succinylcholine, Pancuronium Used to: relax skeletal muscle facilitate intubation ** insure immobility Reversed by neostigmine* & glycopyrrolate * during post-op period * quaternary drugs; ** intubation is usually needed for airway maintenance & to prevent aspiration.

42. Dantrolene Interfers with the release of calcium from the sarcoplasmic reticulum through the SR calcium channel complex. Used to prevent or reverse malignant hyperthermia (which is otherwise fatal in ~50% of cases w/o dantrolene). Given by i.v. push at the onset of symptoms (e.g. an unexpected rise in CO 2 levels ) Supportive measures & 100% O 2 are also used to treat malignant hyperthermia

43. Nausea & Vomiting General anesthetics effect the chemoreceptor trigger zone & brainstem vomiting center (cause nausea & vomiting) Rx: - Ondansetron (5-HT 3 antagonist) to prevent - Avoidance of N 2 O - Propofol for induction - Keterolac vs. opioid for analgesia - Droperidol , metaclopromide & dexamethasone

44. The End